EPEC: Like ETEC, EPEC is essentially a pathogen of the small intestine. In the case of EPEC, and to a lesser extent EHEC, a similar situation exists to that described above for V cholerae. There has been a recent explosion of new molecular biological data; an appreciation of the biological significance follows. EPEC was the first serotype of E coli to be incriminated as a pathogen. Its designation as EPEC is unfortunate because all pathogenic E coli are in a real sense enteropathogenic, but the nomenclature is rigidly embedded. It is essentially a noninvasive pathogen with only rare reports of its presence inside human gut epithelial cells; it can, however, be internalized by cultured cells. Buy Asthma Inhalers Online
The pathognomonic lesion of EPEC is the pedestal type ‘attaching and effacing’ (A/E) lesion induced on microvilli-bearing enterocytes, resulting in ‘intimate’ type of adherence (Figure 5). There are two main genetic elements that confer virulence on EPEC: bfp genes (bundle forming pili [BFP] encoded in the EPEC adherence factor [EAF] plasmid) and the genes encoding the determinants of A/E encoded in the chromosomally located locus of the entero-cyte effacement (LEE) pathogenicity island. BFP have been shown in human volunteer studies to be important, although not absolutely necessary, in the colonization of EPEC; their expression is regulated by the per (plasmidencoded regulator) genes located in the EAF plasmid. The per regulator also controls expression of other membrane proteins and thus acts as a global regulator, a feature now increasingly recognized in pathogenic bacteria. Upon contact with epithelial cells, expression of LEE is triggered. A speculative synthesis of the genetic and ultrastructural data suggests the following (Figure 6). Initial contact of EPEC with epithelial cells is via BFP. Bacterial/target cell contact triggers expression of an LEE-encoded type III secretion system, resulting in the secretion of different subsets of proteins with different functions. (There are at least four mechanisms for secreting proteins from Gram-negative bacteria, designated types I, II, III and IV). Organisms known to have the type III system include Yersinia, Shigella, E coli and Salmonella species. Its main features are that it is expressed in response to an environmental signal such as contact with eukaryotic cell membranes; it translocates proteins from bacterial cytoplasm across cytoplasmic and outer membranes; and in some cases a subset of type III-secreted proteins are assembled into a ‘translocon’ apparatus or ‘molecular syringe’ for delivering other effector proteins into epithelial or phagocytic target cells. Some are involved in the synthesis of the ‘translocon’ apparatus constructed from proteins that form pores in both the bacterial outer membrane and the host cell membrane. These pores are connected by a cylindrical structure comprising other LEE-encoded proteins, and the whole structure acts as a molecular syringe through which bacterial translocated intimin receptor (Tir) is inserted into the host cell membrane. Together with a host cell coreceptor, Tir interacts with the EPEC outer membrane protein intimin, resulting in the intimate binding of the bacterium to the cell membrane, which gives rise to the characteristic pedestal and deformed brush border. Tir is thus a multidomain protein; interaction with intimin results in cytoskeletal rearrangement of the host cell, the formation of the characteristic pedestal and the transduction of signals leading to fluid loss. Such brilliant molecular biological studies have taken us thus far, but no further; the specific signal transductions, how precisely they are generated and how they act to cause diarrhea are not known. However, the dramatic onset of diarrhea seen in volunteer studies — 2.9 h after inge stion of bacteria— strongly indicates the involvement of an active secretory mechanism. The prolonged diarrhea could well be due to the loss of functional brush border, where the transport systems are located. The significance of EAST1, found in some strains of EPEC is not known.
Figure 5) Enteropathogenic Escherichia coli (EPEC) intimate adhesion. Reproduced with permission from reference 100
Figure 6) Schematic representation of the molecular events giving rise to the enteropathogenic Escherichia coli (EPEC)-induced pedestal. Reproduced with permission from reference 20. ESc E coli secretory proteins forming part of the type III secretion system; Esp E coli secreted proteins; Tir Translocated intimin receptor